19-12893531-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000159.4(GCDH):​c.383G>A​(p.Arg128Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R128G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

GCDH
NM_000159.4 missense

Scores

10
6
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 6.33
Variant links:
Genes affected
GCDH (HGNC:4189): (glutaryl-CoA dehydrogenase) The protein encoded by this gene belongs to the acyl-CoA dehydrogenase family. It catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-hydroxylysine, and L-tryptophan metabolism. It uses electron transfer flavoprotein as its electron acceptor. The enzyme exists in the mitochondrial matrix as a homotetramer of 45-kD subunits. Mutations in this gene result in the metabolic disorder glutaric aciduria type 1, which is also known as glutaric acidemia type I. Alternative splicing of this gene results in multiple transcript variants. A related pseudogene has been identified on chromosome 12. [provided by RefSeq, Mar 2013]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1
In a helix (size 11) in uniprot entity GCDH_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_000159.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.909
PP5
Variant 19-12893531-G-A is Pathogenic according to our data. Variant chr19-12893531-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12893531-G-A is described in Lovd as [Pathogenic]. Variant chr19-12893531-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GCDHNM_000159.4 linkuse as main transcriptc.383G>A p.Arg128Gln missense_variant 6/12 ENST00000222214.10 NP_000150.1
GCDHNM_013976.5 linkuse as main transcriptc.383G>A p.Arg128Gln missense_variant 6/12 NP_039663.1
GCDHNR_102316.1 linkuse as main transcriptn.546G>A non_coding_transcript_exon_variant 6/12
GCDHNR_102317.1 linkuse as main transcriptn.799G>A non_coding_transcript_exon_variant 5/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GCDHENST00000222214.10 linkuse as main transcriptc.383G>A p.Arg128Gln missense_variant 6/121 NM_000159.4 ENSP00000222214 P1Q92947-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152136
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251442
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135912
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000109
AC:
16
AN:
1461602
Hom.:
0
Cov.:
31
AF XY:
0.00000963
AC XY:
7
AN XY:
727118
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000117
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152136
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000432
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:8
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteOct 19, 2020Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 5-Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with glutaricaciduria, type I (MIM#231670). Dominant-negative has also been suggested as a mechanism for this gene, however, there is currently limited evidence demonstrating this (GeneReviews). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (6 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Acyl-CoA dehydrogenase, N-terminal domain (PDB). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Arg128Gly) variant has informative conservation and has been previously been reported as a pathogenic variant (PMID: 9711871). (N) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in multiple individuals with glutaricaciduria, type I (MIM#231670) (PMIDs: 18459892; 10699052; 21176883; 31062211; 32508882) (SP). 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 08, 2022Variant summary: GCDH c.383G>A (p.Arg128Gln) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251442 control chromosomes (gnomAD). c.383G>A has been reported in the literature in multiple individuals affected with Glutaric Acidemia Type 1, including at least 3 homozygotes (Zschocke_2000, Boy_2017, Tamhankar_2020) and several compound heterozygotes (e.g. Zschocke_2000, Mushimoto_2011, Boy_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: two have classified the variant as likely pathogenic and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 19, 2023This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 128 of the GCDH protein (p.Arg128Gln). This variant is present in population databases (rs755586631, gnomAD 0.006%). This missense change has been observed in individual(s) with glutaric acidemia type I (PMID: 10699052, 15505393, 19433437, 21176883, 28438223). ClinVar contains an entry for this variant (Variation ID: 189063). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GCDH protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Likely pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityOct 07, 2021- -
Likely pathogenic, criteria provided, single submitterliterature onlyCounsylNov 14, 2014- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 28, 2024- -
Likely pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.96
D;.;D;D
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.89
.;D;D;D
M_CAP
Pathogenic
0.76
D
MetaRNN
Pathogenic
0.91
D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.2
M;.;M;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.52
T
PROVEAN
Uncertain
-3.5
D;.;.;.
REVEL
Pathogenic
0.95
Sift
Uncertain
0.0040
D;.;.;.
Sift4G
Benign
0.39
T;T;T;T
Polyphen
1.0
D;.;D;.
Vest4
0.66
MVP
0.98
MPC
0.74
ClinPred
0.85
D
GERP RS
4.2
Varity_R
0.76
gMVP
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs755586631; hg19: chr19-13004345; COSMIC: COSV105027860; COSMIC: COSV105027860; API